The present invention relates generally to an improved method for treating a host with taxol. More specifically, the present inventive method pertains to the treatment of cancerous tumors in humans, especially ovarian tumors, with taxol.
Significant strides have been made in the treatment of advanced stage cancers over the past few years. One of these advances centers around the introduction of cisplatin into treatment regimens for ovarian cancer. Despite such advances, however, the number of patients experiencing long-term disease-free periods after receiving such platinum-based therapy remains under 20 percent (Young et al., xe2x80x9cCancer Of The Ovaryxe2x80x9d in Cancer Principles and Practice of Oncology (DeVita et al., Eds., J. B. Lippincott Co., Philadelphia), 1162-96 (1989); Rothenberg et al., Med. J. Australia, 148, 354-63 (1988)). While these results are encouraging, they nevertheless underscore the need for the discovery of more effective agents and regimens useful in treating solid cancerous tumors.
Taxol has been identified as one such new agent. This agent is derived from the bark of the Western Yew tree, taxus brevifolia (Chabner, PPO Update, 5 (9), 1-10 (1991); Rowinsky et al., J. Nat""Cancer Inst., 82, 1247-1259 (1990)). Studies to date have indicated that taxol within a dose range of 110 to 200 mg/m2 has produced objective responses in about 30 percent of patients having cisplatin-sensitive and cisplatin-resistant advanced stage epithelial ovarian cancer (McGuire et al., Ann. Intern. Med., 11, 273-79 (1989); Thigpen et al., Proceedings ASCO, 9, 156 (Abst. 604) (1990); Einzig et al, Proceedings AACR, 31, 187 (Abst. 1114) (1990)). Indeed, taxol is the only agent with proven efficacy for patients with platinum-resistant ovarian cancer.
However, despite taxol""s promise, there is a limit to the amount of taxol that can be used in any treatment regimen. More specifically, when taxol is administered in a treatment regimen for solid tumors, patients experience myelosuppression i.e., bone marrow suppression which includes neutropenia, anemia, and thrombocytopenia, at elevated taxol levels. This myelosuppression is dose-limiting, hence the maximum quantity of taxol that is recommended to be used in the treatment of solid tumors is 175 mg per square meter of body area every 21 days (mg/m2/ 21 days) (Donehower et al., Cancer Treat. Rpt., 71, 1171-77 (1987); Wiernik et al., Cancer Res., 47, 2486-93 (1987); Wiernik et al., J. Clin. Oncol., 5, 1232-39 (1987)).
Other problems in addition to myelosuppression appear when dosage levels of taxol over the previously identified maximum are administered. As the taxol dosage level is increased to levels above about 175-200 mg/m2/ 21 days, a further dose-limiting toxicity, mucositis, is encountered. Mucositis is an inflammation of the lining of the gastrointestinal tract which may result in mouth sores, painful diarrhea, and rectal soreness. Eventually, with yet higher dosage levels of taxol, e.g., above about 300 mg/m2/ 21 days, severe neurotoxicity in the form of peripheral neuropathy is experienced (Rowinsky et al., Cancer Res., 49,4640-47 (1989); Lipton et al., Neurology, 39,368-73 (1989)).
The aforesaid potentially severe consequences which arise when taxol is administered at dosages above about 175 mg/m2/ 21 days have prevented even the clinical investigation of the therapeutic effect of taxol at dosages in excess of that level.
Accordingly, there exists a need for a means to alleviate or prevent the adverse side-effects attendant the administration of taxol in high doses so as to enable an evaluation of the therapeutic effects of taxol at dosage levels above the dose-limiting amount presently able to be safely administered. Similarly, there is a need for a method of providing a relatively safe and effective regimen using taxol for the treatment of cancerous solid tumors, particularly ovarian tumors, without the attendant side-effects of myelosuppression, mucositis, and other toxicities.
These needs are satisfied with the method of the present invention. In particular, it is an object of the present invention to provide a means of enabling the evaluation of the therapeutic benefits of taxol while alleviating or preventing myelosuppression, mucositis, and other toxicities. It is a further object of the present invention to provide a safe and effective regimen utilizing taxol for the treatment of cancerous tumors.
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a method of treating a host using taxol comprising administering granulocyte colony-stimulating factor to a host being treated with taxol. The invention advantageously provides for the treatment of a host with taxol in an amount greater than currently being used and which would otherwise be sufficient to cause myelosuppression or mucositis if not administered in conjunction with the administration of a granulocyte colony-stimulating factor. In accordance with the present invention, granulocyte colony-stimulating factor is administered in an amount effective to alleviate or prevent myelosuppression (e.g., neutropenia), and most preferably, mucositis. The invention provides an improved method for the treatment of cancerous tumors, e.g., breast, lung, and particularly ovarian tumors, with taxol.
The method of the present invention provides a means for treating a host who is undergoing therapy with the pharmaceutical drug taxol. In particular, the present inventive method comprises administering granulocyte colony-stimulating factor (G-CSF) to a host being treated with taxol. The term taxol as used herein and in the appended claims encompasses taxol per se as well as all water-soluble derivatives thereof, particularly water-soluble taxol derivatives, such as, for example, 2xe2x80x2-succinyl-taxol, 2xe2x80x2-succinyl-taxol triethanolamine, 2xe2x80x2-glutaryl-taxol, 2xe2x80x2-glutaryl-taxol triethanolamine salt, 2xe2x80x2-with N-(dimethylaminoethyl) glutamide, and 2xe2x80x2-O-ester with N-(dimethylaminoethyl) glutamide hydrochloride salt. Examples of taxol compounds and methods for their preparation are set forth in U.S. Pat. No. 4,942,184. U.S. Pat. No. 5,104,651 provides further information regarding G-CSF and pharmaceutical formulations thereof. G-CSF is available from Amgen, Inc. of Thousand Oaks, Calif.
The present inventive method advantageously provides a means by which taxol may be administered to a host during a treatment regimen in an amount sufficient to cause myelosuppression (e.g., neutropenia with or without fever) or mucositis if not administered in conjunction with the administration of G-CSF. In other words, taxol can now be administered in excess of the current dose-limiting amount, i.e., in excess of about 175 mg/m2/ 21 days.
Generally, G-CSF is administered to the host being treated with taxol in an amount effective to either alleviate or prevent myelosuppression or mucositis. The amount of G-CSF which will provide the aforesaid benefits will vary somewhat depending on the particular host.
5 Typically, the amount of G-CSF administered will be about 5 xcexcg/kg/day and more typically from about 10 to about 20 xcexcg/kg/day for at least about seven days of each 21 day taxol treatment cycle.
The present invention further provides a novel variable dosing regimen for G-CSF wherein the G-CSF dose intensity is varied based upon the symptoms exhibited by the patient during taxol treatment. For example, if the patient develops neutropenia during a cycle of therapy, instead of addressing this in the conventional mannerxe2x80x94by reducing the taxol dose intensity after that cycle of therapyxe2x80x94the present inventive method calls for an increase in G-CSF dose intensity during the subsequent cycle. This enables the taxol dose intensity to be maintained at the same level during the subsequent cycle. In view of this discovery, and assuming, for example, neutropenia is experienced by a patient, the G-CSF dose intensity, which would typically be administered at a level of about 10 xcexcg/kg/day for a patient receiving taxol at a dosage level of about 250 mg/m2/ 21 days, would advantageously be increased to a level ranging from about 10-20 xcexcg/kg/day, and preferably to a level ranging from about 15-20 xcexcg/kg/day. This increase would allow the taxol dose intensity in a subsequent cycle or cycles to remain at the 250 mg/m2/ 21 days level.
A typical taxol treatment regimen in accordance with the present invention therefore comprises administering taxol once every three weeks in conjunction with the daily administration of G-CSF. Preferably, the host is treated with taxol in an amount of about 200 to about 250 mg/m2/ 21 days, and G-CSF is administered in an amount of about 10 to about 20 xcexcg/kg/day for about seven days of the taxol cycle. If the CSF dose of 10 xcexcg/kg/day is poorly tolerated (as occurs in about 5% of patients), the G-CSF dose can be reduced to about 5 xcexcg/kg/day.
While the method of the present invention is effective with respect to any use of taxol, it is particularly well-suited in treating cancerous tumors in a host, especially ovarian, breast, and lung cancers. The present inventive method is particularly useful in the treatment of cancerous ovarian tumors.
The present invention provides for the raising of the current standard dose-limiting level of taxol from about 175 mg/m2/ 21 days to about 250 mg/m2/ 21 days and perhaps as high as 300 mg/m2/ 21 days. Moreover, the invention provides a means by which the typical or xe2x80x9cstandardxe2x80x9d dose of taxol can be increased from the current level of about 135 mg/m2/ 21 days to about 250 mg/m2/ 21 days. The present invention, therefore, provides for an approximately 40-85% increase in the amount of taxol that can be safely administered to a host. This increase in the level of taxol corresponds to an increase in the objective response of cancerous tumors and, in particular ovarian cancer. With the xe2x80x9cstandardxe2x80x9d dose of taxol, the objective response rate is about 30%. When administering taxol at a dosage of about 250 mg/m2/ 21 days, the objective response rate is about 50% (a 67% increase in the response rate).
It was at the 300 mg/m2/ 21 days taxol level that, even with the administration of G-CSF, the dose-limiting symptoms of peripheral neuropathy of grade 3 were detected. Grade 3 peripheral neuropathy is defined for the purposes of describing the present invention as the occurrence of a functional deficit (e.g., difficulty in the use of the hands or unsteadiness of gait) accompanied by diminution in reflexes and distal dysesthesia or sensory loss. While substantial myelosuppression can be observed with the administration of such high dose levels of taxol in accordance with the present invention, such myelosuppression is not dose-limiting. Moreover, mucositis is rarely observed at these higher taxol levels achieved as a result of the present invention.
The following examples further illustrate the present invention and should not be construed in any manner to limit its scope.